Grantsmanship – Hypothesis Generation and Testing H. F. Gilbert

Outline Hypothesis driven and discovery driven science Coming up with models/hypotheses and ways to test their predictions The Abstract and Specific Aims

A tumor-specific endonuclease You have just isolated and purified an endonuclease that is over-expressed specifically in estrogen-dependent tumor cell lines. It cleaves specifically at the junction of a single-double stranded region of DNA. +

How would you investigate this endonuclease further?

Science A collection of facts & observations models that predict A method to construct models that predict the way the world works We want to determine the DNA sequence of the human genome We want to genotype cancer patients We want to know all proteins that interact with X Non-hypothesis driven scienceHypothesis-driven science Alberts, et al Mol. Biol. of Cell

The Scientific Method ObservationsHypothesis or Model Predictions Experiments falsifiable controls Truth

Thought Processes for Hypothesis- Generation 1. What is it that I don’t understand about some experimental observations (yours or others) based on what I already know about how the world works - I don’t understand (make a list) 2. What is already known that I don’t know - this is a search of the literature to find out what is already known 3. #count list 1 - #count list 2 - if <=0 then find another set of observations to wonder about

Thought Processes for Hypothesis- Generation 4. What is a likely explanation (model) that could account for the experimental observations. Why are you thinking this (rationale) I think that..... happens because I know that – the explanation should be reasonable based on what you and others know already (extraordinary explanations require extraordinary experimental verification) –it should be sufficient to account for the unexplained behavior/observation –you should be able to draw it with balls and sticks (or math) –you should consider any other likely model

Thought Processes for Hypothesis- Generation 4. What predictions does your model make If my model is correct then if I do then should happen –prediction should be able to falsify your model, i.e. if the predicted result is not obtained it should show that your model is wrong –prediction should lead to a clear experiment that would distinguish your model from other likely models 5. Does the observation generate any new hypotheses

Specific Aims Designed to capture how you think –How knowledgeable you are about current thinking/models –How well you can assemble known facts into a model/hypothesis that can describe something that is not known –How well you can design experiments and controls to critically test your model

Specific Aims Summarize the WHOLE GRANT in 1 page Don’t make the reviewer think/guess Consider who/how/process of review –Write for a generally well-informed scientist, NOT AN EXPERT –Grab reviewer’s attention – significance, logic, approach –avoid words like novel, exciting, first-time, prove, routine, characterize –use words like model, hypothesis, test, predict, analyze, control

Specific Aims Page 1 st paragraph –general significance of research –health relatedness (mention specific diseases) –how your research fits in with the above 2 nd paragraph –state long-term goal of research –describe your model(s)/hypothesis (es) and why you think it’s a good model (i.e. rationale for the hypothesis) –what will we know when you’ve completed the research keep at about ½ page

Specific Aims Page 3 rd -7th paragraphs (3-4 specific aims) –Give each specific aim a short title so you can refer to them later –Include, in 3-4 sentences what part of the model does this aim test what does the model predict (rationale) what experiments will be done and how data will be analyzed how the potential/likely results provides a critical test of the validity of the model what you will know that wasn’t know before when the experiments and analysis are complete –Last paragraph restate significance and how your proposed experiments, when completed, will add to knowledge, ability, understanding

Specific Aim Paragraph 1 st sentence –“The model/hypothesis predicts/suggests..” –“Experiments in this aim will test... –“XXX and YYY are known so ZZZ (unknown) is likely correct,,

Next steps Write and re-write for clarity and conciseness Share with colleagues for their comments Write the grant to parallel the specific aims page Iteratively change grant and specific aims to produce a consistent presentation of your thought processes

A tumor-specific endonuclease You have just isolated and purified an endonuclease that is over-expressed specifically in estrogen-dependent tumor cell lines. It cleaves specifically at the junction of a single-double stranded region of DNA. +

Now design a specific aims page